a-Tocopheryl succinate (a-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of a-TOS has not been identified. Here, we show that a-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of a-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of a-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to a-TOS. We propose that a-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

Antigen-specific suppression of a previously primed immune response is a major challenge for immunotherapy of autoimmune disease. RelB activation is required for myeloid DC differentiation. Here, we show that antigen-exposed DCs in which RelB function is inhibited lack cell surface CD40, prevent priming of immunity, and suppress previously primed immune responses. DCs generated from CD40-deficient mice similarly confer suppression. Regulatory CD4+ T cells induced by the DCs transfer antigen-specific "infectious" tolerance to primed recipients in an interleukin-10-dependent fashion. Thus CD40, regulated by RelB activity, determines the consequences of antigen presentation by myeloid DCs. These observations have significance for autoimmune immunotherapy and suggest a mechanism by which peripheral tolerance might be constitutively maintained by RelB(-) CD40(-) DCs.

The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by ␣-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redoxsilence is a prerequisite property for most of the anticancer activities described in this communication.Despite advances in molecular medicine, the third millennium has borne witness to neoplastic disease becoming a major cause for mortality in developed countries. Moreover, fast-growing economies in countries like India and China are likely to be severely affected by cancer in a decade or so as a result of heavy industrialization. Certain types of cancer, such as malignant mesothelioma (MM), seem to remain beyond the realms of treatment. In many other cases, mutations arise in the tumors, seriously compromising the outcome of the therapy. For example, in breast cancer, in which a high frequency of overexpression of the tyrosine receptor kinase erbB2 occurs, this is often associated with resistance to chemotherapy (Xia et al., 2006). We are therefore in need of treatment modalities that would overcome these problems and that are efficient, selective, and readily available to all Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.106.030122.ABBREVIATIONS: MM, malignant mesothelioma; BH, Bcl-2 homology; DHFR, dihydrofolate reductase; DR, death receptor; ERK, extracellular signal-regulated protein kinase; FLIP, Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein; IAP, inhibitor of apoptosis protein; IB, inhibitory subunit of nuclear factor B; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPTP, mitochondrial permeability transition pore; MTX, methotrexate; NFB, nuclear factor-B; O...

Mitochondria have emerged recently as effective targets for novel anti-cancer drugs referred to as 'mitocans'. We propose that the molecular mechanism of induction of apoptosis by mitocans, as exemplified by the drug a-tocopheryl succinate, involves generation of reactive oxygen species (ROS). ROS then mediate the formation of disufide bridges between cytosolic Bax monomers, resulting in the formation of mitochondrial outer membrane channels. ROS also cause oxidation of cardiolipin, triggering the release of cytochrome c and its translocation via the activated Bax channels. This model may provide a general mechanism for the action of inducers of apoptosis and anticancer drugs, mitocans, targeting mitochondria via ROS production.

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Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic A-tocopheryl succinate (A-TOS). Treating erbB2-low or erbB2-high cells with A-TOS induced similar levels of apoptosis, whereas A-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. A-TOS rapidly accumulated in erbB2-high cells exposed to A-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by A-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. A-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting A-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors.

Mitochondria are proving to be worthy targets for activating specific killing of cancer cells in tumors and a diverse range of mitochondrial targeted drugs are currently in clinical trial to determine their effectiveness as anti-cancer therapies. The mechanism of action of mitochondrial targeted anti-cancer drugs relies on their ability to disrupt the energy producing systems of cancer cell mitochondria, leading to increased reactive oxygen species and activation of the mitochondrial dependent cell death signaling pathways inside cancer cells. We propose that this emerging class of drugs be called "mitocans", a term that reflects their mitochondrial targeting and anti-cancer roles. They are discussed in this review in the context of their mode of action whereby they target the functional differences and altered properties of the mitochondria inside cancerous but not normal cells. Hence, mitocans include drugs affecting the following mitochondrial associated activities: hexokinase inhibitors; electron transport/respiratory chain blockers; activators of the mitochondrial membrane permeability transition pore targeting constituent protein subunits, either the voltage dependent anion-selective channel (VDAC) or adenine nucleotide transporter (ANT); inhibitors of Bcl-2 anti-apoptotic family proteins and Bax/Bid pro-apoptotic mimetics. In particular, a recent surge has occurred in the number of patent documents describing small molecule inhibitors and BH3 mimetic blockers of Bcl-2/Bcl-x(L) function as obvious and important targets for promoting mitochondrial induced cancer cell death and for enhancing the actions of other chemotherapeutic agents. One of the other highly significant results to emerge from clinical applications of mitochondrial targeted drugs as cancer therapies to date is that they have shown limited side-effects on the normal "healthy" cell populations in vivo. It is still too early to judge the clinical impact that mitocans will make in treating cancer. Further clinical studies will be required before these novel drugs become established as single modality anti-cancer therapies or are used in conjunction with existing chemotherapies. However, it is clear from the present studies that mitocans offer great potential as effective and exciting new developments in cancer therapy, providing direct activation of cancer cell death by mitochondrial mediated apoptosis and that this complements the other pathways by which existing treatments kill cancer cells. Undoubtedly, mitocans will become an integral part of modern weaponry in the fight to eliminate cancer.